The present invention relates bicyclic nitroimidazole-substituted phenyl oxazolidinones wherein a bicyclic nitroimidazole pharmacophore is chemically linked with a phenyl oxazolidinone pharmacophore via a covalent bond.
The disturbing increase in bacterial resistance to existing antibacterial agents is a major clinical challenge. Accordingly, there is a need in the art for compounds, compositions, and methods of treating warm-blooded animals that suffer from a bacterial infection and are resistant to conventional antibacterial treatments. The rise of multidrug-resistant tuberculosis (“MDRTB”) is a profound public threat. Tuberculosis (“TB”) is highly contagious. The caustic pathogenic Mycobacterium tuberculosis bacteria are easily passed from person to person in airborne droplets formed when a person with active TB sneezes or coughs. MDRTB is extraordinarily difficult to treat, and a majority of patients do not respond to conventional therapy. Total treatment costs for an individual with MDRTB can be as much as 10 times the cost of traditional treatment, and the cost of the treatment drugs alone can be as much as 21 times as great. The preferred treatment for classical TB consists of isoniazid, rifampin, pyrazinamide and ethambutol, four drugs combination in the first two month of intense treatment phase, followed by four month of second phase of treatment with rifampin and isoniazid two drug cocktail. MDRTB patients require specialized treatment with additional medications, which may include streptomycin and ciprofloxacin for almost two years.
Bicyclic nitroimidazoles are known antibacterials, and they are potent agents against Mycobacterium tuberculosis bacteria. A series of nitroimidazo[2,1-b]oxazole derivates are reported to exhibit antimicrobial properties, including antitubercular activity (Nagarajan, K. 1989). The compound of formula (a) in which R is ethyl, (i.e. 2-ethyl-5-nitro-2,3-dihydro[2,1-b]imidazo-oxazole, also known as CGI 17341) has been shown to exhibit activity against Mycobacterium tuberculosis (Ashtekar, D. 1993). More recently, 2,3-dihydro-6-nitroimidazo[2,1-b]oxazoles (WO 2005/042542 A1 and Sasaki, H. 2006) described by formula (b) were disclosed as agents for the treatment of tuberculosis, wherein R1 represents H, alkyls etc.; R2 is alkoxy, aryloxy etc. Another class of bicyclic nitroimidazoles is nitro-[2,1-b]imidazopyran compounds, which are reported to exhibit antimicrobial properties, including antitubercular activity (U.S. Pat. No. 6,087,358), as shown by formula (c), wherein R1 and R2 are various alkyloxy or aryloxy substituents; X is O, S, NR2 etc.; Y, Z are CH2, CHR2 and heteroatoms etc.

Oxazolidinones are a new class of synthetic antimicrobial agents which kill gram positive pathogens by inhibiting a very early stage of protein synthesis. Oxazolidinones inhibit the formation of ribosomal initiation complex involving 30S and 50S ribosomes leading to prevention of initiation complex formation. Due to their novel mechanism of action, these compounds are active against pathogens resistant to other clinically prescribed antibiotics. WO2006043121 discloses heteroaryl-substituted piperazinyl phenyl oxazolidinones; U.S. Pat. No. 5,736,545 describes azolyl piperazinyl phenyl oxazolidinones; U.S. Pat. No. 5,880,118 discloses substituted oxazine and thiazine oxazolidinone antimicrobials. U.S. Pat. No. 6,968,962 discloses phenyloxazolidinones having a C—C bond to 4-8 membered heterocyclic rings. U.S. Pat. No. 5,981,528 discloses antibiotic oxazolidinone derivatives.
Other earlier publications in the area of oxazolidinones are U.S. Pat. Nos. 4,801,600, 4,921,869, EPA 0352781 (Jan. 31, 1989) and EPA 0316594 (May 24, 1989).
Although oxazolidinones and bicyclic nitroimidazoles are known, there are no references that disclose covalently bonding a phenyl oxazolidinone to a bicyclic nitroimidazole pharmacophore and using the resulting bicyclic nitroimidazole-substituted phenyl oxazolidinones as anti-bacterial agents against aerobic and anaerobic Gram-positive and Gram-negative bacteria, especially mycobacteria and clostridia.